Animals and humans infected with the bloodfluke Schistosoma mansoni generate specific immune responses to glycan antigens. We have shown that anti-glycan antibodies can cause complementdependent lysis of newly transformed schistosomula, raising hopes that a vaccine containing glycoconjugates might be effective in preventing or limiting infection of naive animals and humans. Our previous studies have also documented many of the antigenic glycans and the development of immune responses to these glycans during infection. Moreover, we have developed novel methods of synthesizing protein conjugates to contain most of the major identified schistosome glycan antigens with the aim of enhancing T-cell dependent immune responses in vaccinated animals. We now propose to exploit the positive developments from our previous funding period to develop a unique set of schistosome glycanprotein conjugates and test their roles in humoral and cellular immune responses and innate immunity toward schistosomiasis in mice. Three specific aims are proposed. Aim 1. We will synthesize novel schistosome-related glycan-protein conjugates containing the carrier proteins hepatitis B capsid protein and the schistosome-derived protein sm14. Aim 2. We will immunize Swiss Webster mice with glycan-protein conjugate sets. Immunized animals will be monitored for glycan specificity, titer and antibody type, and for their ability to kill schistosomula in a complement-dependent manner. We will characterize the cellular immune response to these conjugates, and define the roles of glycans, by in vivo and in vitro approaches. We will investigate the innate immune response and define mechanisms by which glycans modulate dendritic cell functions to polarize the adaptive immune response, and identify the receptors on dendritic cells mediating these effects. Aim 3. We will challenge appropriately immunized animals with S. mansoni cercariae and assess the in vivo protective capacity of the most effective conjugates defined in Aim 2. We will measure worm burdens and study liver histopathology, and define leukocyte recruitment, including eosinophils, to lung (bronchoalveolar lavage - BAL). We will also measure antibody classes and titers in sera and BAL from challenged and control mice. These studies will provide important new insights into the immune responses to glycan antigens in parasitic infections and test the potential of glycan-protein conjugates as vaccine candidates for parasitic helminths.